The face of aging in the United States is changing dramatically with the projection of 70 million Americans age 65 or older in the next 25 years. As life expectancy increases, the incidence of diseases such as cancer, cardiovascular disorders and neurodegeneration rises. It is vital, therefore, that we understand more about the dynamics of aging, how they interact with various environmental and lifestyle factors, and the connections between disease processes and aging in order to develop more effective ways to prevent, diagnose and treat age-related diseases. Our recent work on environmental enrichment, a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, enhanced insulin sensitivity, enhanced immune function, and inhibition in cancer growth. Moreover the anti-cancer and anti-obesity phenotypes are mediated by the activation of a brain-fat axis, the hypothalamic-sympathoneural-adipocyte (HSA) axis. In this regulatory network, the key component in the brain is BDNF, which is highly responsive to activity and the environment, and it controls the HSA activity and thereby regulates fat. Fat, as the principal responsive organ in the periphery, subsequently influences multiple organ systems. The key features of activation of the HSA axis are shared by those environmental and genetic factors known to increase lifespan such as calorie restriction and fat-specific insulin receptor knockout mice. However the role of the HSA axis in the aging process has not been investigated. The long-term goal of this study is to understand how a physically, mentally, and socially active environment may influence healthspan and lifespan and to define the underlying mechanisms. Specifically, we propose to utilize a multidisciplinary approach to characterize the role of HSA axis in healthy aging. We plan to investigate the effects of short-term activation of the HSA axis via environmental intervention or gene transfer of BDNF on aging markers (adiposity, metabolism, hormonal and growth factor alteration, insulin sensitivity, and immune function), as well as the effects of long term HSA axis activation on healthspan and lifespan in both normal animals and obesity and diabetes models. Accomplishing the proposed experiments will assess the role of this newly characterized brain-fat axis in healthy aging and the effects of manipulating a single gene in the brain to regulate healthspan, and furthermore may reveal potential targets for the prevention and treatment of age-related diseases.